Synthesis and biological activity of medium molecular weight polymers of camptothecin Neung-Ju Lee a, * , Sung-Suk Ju b , Won-Jei Cho b , Seon-Hee Kim c , Kyung-Tae Kang d , Thomas Brady e , Emmanuel A. Theodorakis e a Department of Premedical Sciences, College of Medicine, Kosin University, Pusan 602-703, South Korea b Department of Polymer Science and Engineering, Pusan National University, Pusan 609-735, South Korea c Department of Biochemistry, College of Medicine, Pusan National University, Pusan 609-735, South Korea d Department of Chemistry, Pusan National University, Pusan 609-735, South Korea e Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA Received 2 January 2002; received in revised form 10 June 2002; accepted 1 August 2002 Abstract A new monomer, 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidohexanoylcamptothecin (ETHCPT) was synthe- sized from 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidohexanoic acid. Its homopolymer and copolymer with acrylic acid (AA) were synthesized and spectroscopically characterized. The ETHCPT content in poly(ETHCPT-co- AA) obtained by elemental analysis was 37 wt.%. The number-average molecular weights of the polymers determined bygelpermeationchromatographywereasfollows: M n ¼ 9700forpoly(ETHCPT), M n ¼ 25500forpoly(ETHCPT-co- AA).TheIC 50 valueofETHCPTanditspolymersagainstcancercellswasmuchlargerthanthatofCPT.The in vivo antitumoractivityofallpolymersinBalb/Cmicebearingthesarcoma180tumorcelllinewasgreaterthanthatofCPT atadoseof100mg/kg. Ó 2002 Elsevier Science Ltd. All rights reserved. Keywords: 3,6-Endo-methylene-1,2,3,6-tetrahydrophthalimidohaxanoylcamptothecin; Camptothecin; Poly(ETHCPT-co-AA); Photo- polymerization; In vitro cytotoxicity; In vivo antitumor activity 1. Introduction Despite their many clinical benefits, anticancer drugs often cause significant side effects due to their overall cytotoxicity and their lack of tissue specificity. In prin- ciple, these issues can be addressed by conjugating the parent drugs to polymers [1–3], thereby enhancing both their tissue specificity and effective concentration at tumorsites.Infact,incontrasttolowmolecularweight anticancer drugs, polymer-based therapeutics have been found to accumulate more in tumor tissues due to an enhanced permeability and retention effect at these sites [4,5].Moreover,theycanprolongtheantitumoractivity oftheparentdrugbyreleasingitatacontrolledrateat the targeted site [6]. The value of the above strategy is illustrated by the numerous studies dealing with conjugation of polymers with drugs such as doxorubicin [7,8], taxol [9,10], neocarzinostatin [11], podophyllotoxin [12] and camptothecin (CPT) [13–16]. Among these compounds the CPT-conjugates are particularly appealing since the parent molecule (CPT) has a well understood mode of action, a well established clinical potential and well documented side effects. More specifically, CPT European Polymer Journal 39 (2003) 367–374 www.elsevier.com/locate/europolj * Corresponding author. Tel.: +82-51-990-6428; fax: +82-51- 241-5458. E-mail address: njlee@ns.kosinmed.or.kr (N.-J. Lee). 0014-3057/02/$ - see front matter Ó 2002 Elsevier Science Ltd. All rights reserved. PII:S0014-3057(02)00219-7